Substituted benz-azoles and methods of their use as inhibitors of Raf kinase

Abstract

New substituted benz-azole compounds, compositions and methods of inhibition of Raf kinase activity in a human or animal subject are provided. The new compounds compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.

1. A compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein, 
         X 1  and X 2  are independently selected from ═N— and —O—, 
         provided that when X 1  is ═N—, X 2  is —O—; when X 2  is ═N—, X 1  is —O—; and X 1  and X 2  are not both O; 
         Y is O or S; 
         A 1  is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl; 
         A 2  is substituted or unsubstituted heteroaryl; 
         R 1  is O and R 2  is NR 5 R 6  or hydroxyl; or R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond, provided that the dashed line in 
       
       
         
           
           
               
               
           
         
         represents a double bond when R 1  is O; 
         R 3  is hydrogen, halogen, loweralkyl, or loweralkoxy; 
         R 5  and R 6  are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R 5  and R 6  are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; and 
         the pharmaceutically acceptable salts, esters and prodrugs thereof. 
       
     
     
       2. A compound of  claim 1  wherein X 1  is —O—, and X 2  is ═N—. 
     
     
       3. A compound of  claim 1  wherein Y is O. 
     
     
       4. A compound of  claim 1  wherein A 1  is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkylfluorophenyl, trifluoromethylchlorophenyl, trifluoromethylbromophenyl, indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceyt1-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone, anilinyl, quinolinyl, quinolinonyl, 9H-fluoren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, pyrimidin-5-ylphenyl, quinolidinyiphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, 1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 
     
     
       5. A compound of  claim 1  wherein A 2  is substituted or unsubstituted pyridyl. 
     
     
       6. A compound of  claim 1  wherein R 1  is O and the dashed line in 
       
         
           
           
               
               
           
         
         represents a double bond. 
       
     
     
       7. A compound of  claim 1  wherein R 2  is NR 5 R 6 , R 5  is hydrogen and R 6  is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl. 
     
     
       8. A compound of  claim 1  wherein R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group. 
     
     
       9. A compound of  claim 1  wherein A 1  is substituted or unsubstituted cycloalkyl. 
     
     
       10. A compound of  claim 1  wherein R 3  is hydrogen. 
     
     
       11. The compound of  claim 1  wherein R 1  is O, R 2  is NR 5 R 6 , R 5  is H, and R 6  is methyl. 
     
     
       12. A compound of the formula (IIIa): 
       
         
           
           
               
               
           
         
         wherein: 
         A 1  is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl; 
         A 2  is substituted or unsubstituted heteroaryl; 
         R 1  is O and R 2  is NR 5 R 6 ; or R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond, provided that the dashed line in 
       
       
         
           
           
               
               
           
         
         represents a double bond when R 1  is O or a single bond when R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; 
         R 3  is hydrogen, halogen, loweralkyl, or loweralkoxy; 
         R 5  and R 6  are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R 5  and R 6  are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; and 
         the pharmaceutically acceptable salts, esters and prodrugs thereof. 
       
     
     
       13. A compound of  claim 12  wherein A 1  is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkylfluorophenyl, trifluoromethylchlorophenyl, trifluoromethylbromophenyl, indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceyt1-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone, anilinyl, quinolinyl, quinolinonyl, 9H-fluoren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, 1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 
     
     
       14. A compound of  claim 12  wherein A 2  is substituted or unsubstituted pyridyl. 
     
     
       15. A compound of  claim 12  wherein R 1  is O and the dashed line 
       
         
           
           
               
               
           
         
         represents a double bond. 
       
     
     
       16. A compound of  claim 12  wherein R 2  is NR 5 R 6 , R 5  is hydrogen and R 6  is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl. 
     
     
       17. A compound of  claim 12  wherein R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group. 
     
     
       18. A compound of  claim 12  wherein R 3  is hydrogen. 
     
     
       19. A compound of  claim 12  wherein R 3  is methoxy. 
     
     
       20. A compound of  claim 12  wherein R 1  is O, R 2  is NR 5 R 6 , R 5  is H, and R 6  is methyl. 
     
     
       21. A compound of the formula (IVa): 
       
         
           
           
               
               
           
         
         wherein Y is O or S; 
         A 1  is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl; 
         R 1  is O and R 2  is NR 5 R 6 ; or R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond, provided that the dashed line in 
       
       
         
           
           
               
               
           
         
         represents a double bond when R 1  is O or a single bond when R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; 
         R 3  is hydrogen, halogen, loweralkyl, or loweralkoxy; 
         R 5  and R 6  are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R 5  and R 6  are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; and 
         the pharmaceutically acceptable salts, esters and prodrugs thereof. 
       
     
     
       22. A compound of  claim 21  wherein Y is O. 
     
     
       23. A compound of  claim 21  wherein A 1  is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkylfluorophenyl, trifluoromethylchlorophenyl, trifluoromethylbromophenyl, indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceyt1-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone, anilinyl, quinolinyl, quinolinonyl, 9H-fluoren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, pyrimidin-5-ylphenyl, quinolidinyiphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, 1,4′-bipiperidin-1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 
     
     
       24. A compound of  claim 21  wherein R 1  is O and the dashed line in 
       
         
           
           
               
               
           
         
         represents a double bond. 
       
     
     
       25. A compound of  claim 21  wherein R 2  is NR 5 R 6 , R 5  is hydrogen and R 6  is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl. 
     
     
       26. A compound of  claim 21  wherein R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group. 
     
     
       27. A compound of  claim 21  wherein R 3  is hydrogen. 
     
     
       28. A compound of  claim 21  wherein R 3  is methoxy. 
     
     
       29. A compound of  claim 21  wherein R 1  is O, R 2  is NR 5 R 6 , R 5  is H, and R 6  is methyl. 
     
     
       30. A compound of the formula (Va): 
       
         
           
           
               
               
           
         
         wherein A 1  is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl; 
         R 1  is O and R 2  is NR 5 R 6 ; or R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the dashed line represents a single or double bond, provided that the dashed line in 
       
       
         
           
           
               
               
           
         
         represents a double bond when R 1  is O or a single bond when R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; 
         R 3  is hydrogen, halogen, loweralkyl, or loweralkoxy; 
         R 5  and R 6  are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R 5  and R 6  are taken together to form substituted or unsubstituted heterocyclo or heteroaryl; and 
         the pharmaceutically acceptable salts, esters and prodrugs thereof. 
       
     
     
       31. A compound of  claim 30  wherein A 1  is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl, pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitrophenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl, dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl, trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkylfluorophenyl, trifluoromethylchlorophenyl, trifluoromethylbromophenyl, indenyl, 2,3-dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceyt1-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, benzophenone, anilinyl, quinolinyl, quinolinonyl, 9H-fluoren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, pyrimidin-5-ylphenyl, quinolidinyiphenyl, furanyl, furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, 1,4′-bipiperidin 1′-yl, and (1,4′-bipiperidin-1′-ylcarbonyl)phenyl. 
     
     
       32. A compound of  claim 30  wherein R 1  is O and the dashed line in 
       
         
           
           
               
               
           
         
         represents a double bond. 
       
     
     
       33. A compound of  claim 30  wherein R 2  is NR 5 R 6 , R 5  is hydrogen and R 6  is selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl. 
     
     
       34. A compound of  claim 30  wherein R 1  is taken together with R 2  to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group. 
     
     
       35. A compound of  claim 30  wherein R 3  is hydrogen. 
     
     
       36. A compound of  claim 30  wherein R 3  is methoxy. 
     
     
       37. A compound of  claim 30  wherein R 1  is O, R 2  is NR 5 R 6 , R 5  is H, and R 6  is methyl. 
     
     
       38. A composition comprising an amount of a compound of  claim 1  effective to inhibit Raf activity in a human or animal subject when administered thereto, together with a pharmaceutically acceptable carrier. 
     
     
       39. A composition of  claim 38  which further comprises at least one additional agent for the treatment of cancer. 
     
     
       40. A composition of  claim 39  in which the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab.